Early Estimate of Nirsevimab Effectiveness for Prevention of Respiratory Syncytial Virus–Associated Hospitalization Among Infants Entering Their First Respiratory Syncytial Virus Season — New Vaccine Surveillance Network, October 2023–February 2024

Respiratory syncytial virus (RSV) is the leading cause of hospitalization among infants in the United States. In August 2023, CDC's Advisory Committee on Immunization Practices recommended nirsevimab, a long-acting monoclonal antibody, for infants aged <8 months to protect against RSV-associated lower respiratory tract infection during their first RSV season and for children aged 8-19 months at increased risk for severe RSV disease. In phase 3 clinical trials, nirsevimab efficacy against RSV-associated lower respiratory tract infection with hospitalization was 81% (95% CI = 62%-90%) through 150 days after receipt; post-introduction effectiveness has not been assessed in the United States. In this analysis, the New Vaccine Surveillance Network evaluated nirsevimab effectiveness against RSV-associated hospitalization among infants in their first RSV season during October 1, 2023-February 29, 2024. Among 699 infants hospitalized with acute respiratory illness, 59 (8%) received nirsevimab ≥7 days before symptom onset. Nirsevimab effectiveness was 90% (95% CI = 75%-96%) against RSV-associated hospitalization with a median time from receipt to symptom onset of 45 days (IQR = 19-76 days). The number of infants who received nirsevimab was too low to stratify by duration from receipt; however, nirsevimab effectiveness is expected to decrease with increasing time after receipt because of antibody decay. Although nirsevimab uptake and the interval from receipt of nirsevimab were limited in this analysis, this early estimate supports the current nirsevimab recommendation for the prevention of severe RSV disease in infants. Infants should be protected by maternal RSV vaccination or infant receipt of nirsevimab.


Introduction
Respiratory syncytial virus (RSV) is the leading cause of hospitalization in U.S. infants, responsible for 50,000-80,000 hospitalizations annually in children aged <5 years (1,2).The * These senior authors contributed equally to this report.highest hospitalization rates occur during the first months of life, and risk declines with increasing age in infancy and during early childhood (3).In August 2023, CDC's Advisory Committee on Immunization Practices (ACIP) recommended nirsevimab, a long-acting monoclonal antibody, for all infants aged <8 months born during or entering their first RSV season, and for children aged 8-19 months at increased risk for severe RSV disease and entering their second RSV season (4).In a pooled analysis of data from prelicensure randomized placebo-controlled clinical trials, 1 dose of nirsevimab given at age <8 months was 79% efficacious against medically attended RSV-associated lower respiratory tract infection and 81% efficacious against RSV-associated lower respiratory tract infection with hospitalization through 150 days after injection (4).In September 2023, a maternal RSV vaccine also became available to prevent RSV disease in young infants.ACIP recommends either nirsevimab or maternal RSV vaccination to protect infants born during or entering their first RSV season (5).In October 2023, in response to nirsevimab shortages, CDC recommended that health care settings with limited supply of nirsevimab prioritize nirsevimab for infants aged <6 months and infants with underlying conditions at highest risk for severe disease (6).In January 2024, additional doses of nirsevimab became available, and CDC recommended that health care settings with adequate nirsevimab supply return to the original ACIP recommendations for nirsevimab use (7).This analysis provides the first U.S. estimate for post-introduction nirsevimab effectiveness among U.S. infants during their first RSV season.

Data Collection and Inclusion Criteria
The New Vaccine Surveillance Network (NVSN) is a population-based, prospective surveillance platform for acute respiratory illness (ARI) in infants, children, and adolescents aged <18 years that monitors pediatric respiratory viruses at seven U.S. pediatric academic medical centers to assess immunization effectiveness.† Demographic, clinical, and immunization data were systematically collected through parent/guardian interviews, medical record abstraction, and state immunization information systems.Respiratory specimens were collected from enrolled children and tested for RSV and other common respiratory viruses by real-time reverse transcription-polymerase chain reaction.§ Receipt of nirsevimab was ascertained through parent report and verified through state immunization information systems, birth hospital, or primary care provider records.¶  Infants were eligible for this analysis if they were aged <8 months as of October 1, 2023, or born after October 1, 2023, were hospitalized with ARI** during October 1, 2023-February 29, 2024, and had verified nirsevimab status, reported gestational age at birth, and medical record review to assess for underlying medical conditions.Infants were excluded if they were enrolled before nirsevimab became available at their site, † † received any doses of palivizumab, had reported maternal RSV vaccination during pregnancy, or inconclusive or unknown RSV test results.For a site to be included in this analysis, at least five infants enrolled at the site had to have received nirsevimab ≥7 days before symptom onset.

Data Analysis
Nirsevimab effectiveness against RSV-associated hospitalization was estimated using a test-negative, case-control design.Case-patients were infants who received a positive RSV test result.Control patients were infants who received a negative RSV test result.Infants were considered nirsevimab recipients if they received nirsevimab ≥7 days before symptom onset to account for RSV incubation period and time to peak antibody † Children's Mercy Hospital, Kansas City, Missouri; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Golisano Children's Hospital, Rochester, New York; Seattle Children's Hospital, Seattle, Washington; Texas Children's Hospital, Houston, Texas; UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania; Vanderbilt University Medical Center, Nashville, Tennessee.§ All enrolled children are tested for the following viruses: adenoviruses, SARS-CoV-2, rhinovirus/enterovirus, RSV, human metapneumovirus, enterovirus-D68, parainfluenza viruses, human coronaviruses, and influenza viruses.¶ Primary care provider record verification was performed in sites without mandatory reporting of nirsevimab administration to state immunization information systems.** ARI is defined as one or more of the following signs or symptoms present for <14 days before enrollment encounter: fever, cough, earache, nasal congestion, runny nose, sore throat, vomiting after coughing, wheezing, shortness of breath, rapid or shallow breathing, apnea, apparent life-threatening event, or brief resolved unexplained event.† † 2023: Houston, Texas, October 5; Nashville, Tennessee, October 8; Seattle, Washington, October 8; Cincinnati, Ohio, October 10; Kansas City, Missouri, November 1; Pittsburgh, Pennsylvania, November 2; Rochester, New York November 6.
concentration.§ § Infants who received nirsevimab <7 days before symptom onset were excluded.Pearson's chi-square tests were used to compare demographic characteristics among case-patients and control patients and by nirsevimab status.Effectiveness was estimated using multivariable logistic regression models, comparing the odds of receipt of nirsevimab among case-patients and control patients.Regression models controlled for age at enrollment in months, month of illness, enrollment site, and presence of one or more high-risk medical conditions for severe RSV disease.¶ ¶ Preterm status (birth at <28, 28-31, 32-33, 34-36, and ≥37 weeks' gestation) and insurance type were evaluated as potential confounders but did not change estimates and were not included in the final model.Effectiveness was calculated as (1− adjusted odds ratio) × 100%.Analyses were conducted using SAS software (version 9.4; SAS Institute).This activity was reviewed by CDC, deemed not research, and was conducted consistent with applicable federal law and CDC policy.***

Discussion
In this multisite analysis of 699 infants hospitalized with ARI during their first RSV season, receipt of nirsevimab was 90% effective against RSV-associated hospitalization at a median of 45 days from receipt of nirsevimab to ARI symptom onset.This early effectiveness estimate supports existing recommendations for the prevention of severe RSV disease in infants in their first RSV season.
The strengths of this first estimate of U.S. post-introduction nirsevimab effectiveness include enrollment of infants using a standardized ARI definition, systematic RSV testing, and receipt of nirsevimab verification with state immunization information systems or medical records for all infants.However, it is important to note that nirsevimab effectiveness during a full RSV season is expected to be lower than the estimate reported here, because antibody levels from passive immunization wane over time.In this analysis, the median interval from receipt of nirsevimab was 45 days, whereas the median duration of the U.S. RSV season before the COVID-19 pandemic was 189 days (8).In clinical trials, nirsevimab remained highly efficacious against RSV-associated lower respiratory tract infection in infants through 150 days after receipt of nirsevimab, consistent with an extended half-life of 63-73 days (9).
Estimating effectiveness under real-world conditions for the full duration of an RSV season and in children aged 8-19 months at high risk for severe RSV disease who are recommended to receive nirsevimab before their second RSV season remains important.Thus, CDC will continue to monitor nirsevimab effectiveness.; or congenital pulmonary abnormalities that impair the ability to clear secretions (none).† † Persons of Hispanic or Latino (Hispanic) origin might be of any race but are categorized as Hispanic; all racial groups are non-Hispanic.

Limitations
The findings in this report are subject to at least five limitations.First, only a small proportion of hospitalized infants with ARI received nirsevimab, likely in part because of delayed availability in this first season of introduction and intermittent supply shortages, and infants who received nirsevimab were more likely to have underlying conditions.§ § § Thus, results might not be fully generalizable to all infants eligible for receipt of nirsevimab in their first RSV season.Second, the low number of case-patients who received nirsevimab did not allow for stratified estimates by time since receipt of nirsevimab.Third, because nirsevimab became available at most sites in the United States after seasonal RSV circulation began, some infants in this analysis might have had RSV infection before receipt of nirsevimab, which might have affected estimated effectiveness.Fourth, nirsevimab effectiveness was not estimated by dosage § § § https://www.cdc.gov/vaccines/imz-managers/coverage/rsvvaxview/index.html (Accessed January 30, 2024).
(50 mg for infants weighing <5 kg or 100 mg for infants weighing ≥5 kg) because nirsevimab dosage was not ascertained.Finally, the effectiveness estimate in this report is limited to the prevention of RSV-associated hospitalization.RSV among infants also causes a considerable increase in outpatient and emergency department visits; additional studies are warranted to assess nirsevimab effectiveness against these outcomes.

Implications for Public Health Practice
Receipt of a single dose of nirsevimab was highly effective against RSV-associated hospitalization in infants entering their first RSV season.This finding supports current CDC recommendations that all infants should be protected by maternal RSV vaccination or infant receipt of nirsevimab, to reduce the risk for RSV-associated hospitalization in their first RSV season (4,6).

FIGURE.
FIGURE.Time from receipt of nirsevimab* to symptom onset among infants born during or entering their first respiratory syncytial virus season who were hospitalized with acute respiratory illness, by respiratory syncytial virus test result -New Vaccine Surveillance Network, October 2023-February 2024